GENETIC BIOCHEMICAL DISORDERS IN MENTAL RETARDATION

The application is for the continued support of a Program Project Grant in
one of the NICHD-funded Mental Retardation Research Centers. The program
comprises five projects whose goal is better understanding of the
biochemical defects and/or pathogenesis of a number of inborn errors which
can result in mental retardation and/or early death. Conditions to be
studied are glutaric acidemia types I and II, homocystinuria due to
cystathionine beta-synthase deficiency and various defects of the
mitochondrial respiratory chain. Drs. Goodman, Frerman and Kraus, the
three BF Stolinsky Laboratories investigators, have common interests and
goals, interact on a daily basis, use the same methods and equipment, and
utilize common tissue culture and recombinant DNA cores of the MRRC. Dr.
Neil Howell, at the University of Texas in Galveston, has been
collaborating with us for several years, and brings longstanding expertise
and interest in the biochemistry and molecular biology of the respiratory
chain to the project. Project I is concerned with glutaric acidemia, a
disorder which causes mental retardation and degeneration of the basal
ganglia, and will examine functional domains of normal glutaryl-coenzyme A
dehydrogenase as well as how normal function is perturbed by naturally
occurring mutations. Projects II and IV focus on the biochemistry and
molecular biology of glutaric acidemia type II (GA2), a disorder which
causes early death and (often) congenital anomalies, examining the effect
of mutations of two proteins (ETF and ETF:QO) whose deficiency causes it.
Project III seeks to identify mutations of the mitochondrial genome in
patients with Leber's Hereditary Optic Neuropathy (LHON) and selected
neuromuscular disorders; and project V will examine genetic heterogeneity
in patients with propionic acidemia and homocystinuria due to deficiency of
cystathionine beta-synthase. All of these projects have the common goal of
eventually understanding how disturbed enzyme function leads to disease,
since such information is essential for formulating rational approaches to
therapy.